Since the completion of the Human Genome Project in 2001, there have been great expectations for translating human genomic information directly into clinically practice. During the last several years, numerous large studies have cataloged human DNA variation. In parallel, advances in DNA sequencing technologies have increased the throughput and decreased costs. We are now positioned to broadly deploy our knowledge of human genetic variation, coupled with high-throughput DNA sequencing methods, for individualized, large-scale medical resequencing to comprehensively reveal the genetic mechanisms underlying disease and influence clinical treatment. This base pairs to bedside translation requires multidisciplinary study. The University of Washington is a leader in clinical genetics (Bennett, Burke, Byers, Hisama, and Jarvik, Motulsky, Raskind, and Sybert), bioethics (Burke, Jarvik, Fullerton, and Trinidad), second-generation sequencing, variant calling and annotation (Rieder and Nickerson), disease gene discovery (Browning, Heagerty, Jarvik, Nickerson, and Rieder), medical informatics (Tarczy-Hornoch), and health services research (Heagerty, Patrick, Regier, and Veenstra). In this highly integrated proposal, we combine these strengths to investigate aspects of using exomic data clinically. We propose a randomized controlled trial of usual care vs. the addition of exome analysis in University of Washington Medical Genetics Clinic patients who have clinical indications for colorectal cancer/polyposis (CRCP) genetic testing. We will evaluate the effectiveness of this technology for the identification of clinically relevant CRCP gene mutations, cost, and patient derived measures. After deliberations by experts to identify variants that are incidental findings that should be returned, we will also return CLIA certified results to the participants. We will obtain structured feedback from subjects in both the usual care and exome arms of the RCT to evaluate their experiences. We will further consider the input of referring physicians and patients using focus groups. We will investigate the legal basis of the need to return CLIA certified research results. An important component of our work is determination of not only which results to return, but how best to incorporate these genomic data into the medical record. Finally, we will perform CRCP gene discovery studies for families without identifiable CRCP mutations; such novel gene discovery can impact prevention and treatment.